1 / 76

Evidence-Based Management of Osteoporosis

Evidence-Based Management of Osteoporosis. A Systematic Review of Agents Currently Available for Osteoporosis and their Use in Clinical Practice. Benefits of Therapy: Summary. Contemporary pharmacologic treatments significantly decrease fracture risk:

elina
Télécharger la présentation

Evidence-Based Management of Osteoporosis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Evidence-Based Managementof Osteoporosis A Systematic Review of Agents Currently Available for Osteoporosis and their Use in Clinical Practice

  2. Benefits of Therapy: Summary Contemporary pharmacologic treatments significantly decrease fracture risk: • “Antiresorptive” therapy produces a modest increase in bone mineral density (BMD) • However, decreases in fracture risk—especially in the spine—occur much faster and to a larger extent than predicted by the relatively small change in BMD. This implies an important improvement in bone “quality” • Anabolic therapy with teriparatide increases BMD more than antiresorptive treatment, but it is not yet obvious that fracture protection is greater

  3. Objective of Intervention The most important clinical objective is the prevention of fractures—both vertebral and non-vertebral fractures Changes in surrogate markers--bone mineral density (BMD) and biochemical markers of bone turnover--are “necessary” but are not “sufficient”

  4. Non-Pharmacological Options • Nutrition: Wide range of nutrients studied • Calcium supplementation as needed (1500 mg total intake) • Vitamin D as needed (400 IU to 800 IU daily) • Exercise: Multiple health benefits • Fall prevention and/or hip protectors in the frail elderly • Other lifestyle modifications • Avoiding alcohol and tobacco abuse

  5. Non-Pharmacological Options • Taken as a whole, non-pharmacological options seem to be relatively inexpensive and modestly effective • Exercise, in particular, has other health benefits, although the same is likely to be true for diet optimization • Optimization of diet, exercise, and fall prevention should be viewed as an important adjunct to the pharmacologic treatment of osteoporotic patients

  6. FDA-Approved Therapeutic Options Treatment Reduces vertebral fractures Prevention Stops bone loss Estrogen Calcitonin(Miacalcin, Fortical) Alendronate(Fosamax) Risedronate(Actonel) Ibandronate(Boniva: oral, injection) Raloxifene (Evista) PTH(Forteo)

  7. Normal Coupling of Bone Remodeling Treatment Agents: Mechanism of Action Resorption = Formation • Most treatment agents (bisphosphonates, SERMs, calcitonin, estrogen) act primarily on the left side of the equation—to decrease bone resorption • A decrease in resorption is followed by a decrease in formation • Only teriparatide acts on the right side of the equation—to stimulate formation

  8. Antiresorptive Treatment: Summary • Antiresorptive treatment produces a decrease in the biochemical markers of bone turnover and a modest increase in BMD • Because a decrease in resorption is followed by a decrease in formation, BMD improvement tends to “plateau” after several years

  9. Antiresorptive Treatment: Summary • Antiresorptive treatment decreases fracture risk much more rapidly and to a larger extent than one would predict from the relatively small changes in BMD Note: Fracture protection can be observed in the absence of a significant change in BMD • Fracture protection persists even when the BMD reaches a plateau • Fracture reduction is most conspicuous in older patients with prevalent vertebral fractures

  10. Antiresorptive Agents: Clinical EfficacyTrials of Different Agents Cannot Be Compared Directly • For the prevention of osteoporosis, agents must demonstrate protection against bone loss—typically in a population of early postmenopausal women • For the treatment of osteoporosis, agents must demonstrate protection against fracture—typically, against vertebral fracture in a population of older postmenopausal women with low BMD, with or without prevalent vertebral fractures • Not every treatment agent has been evaluated in a clinical trial with sufficient statistical power to examine protection against nonvertebral fracture. in general—or hip fracture, in particular

  11. Calcium and Vitamin D Reduce Nonvertebral Fracture Incidence 15 Placebo Calcium-vitamin D P = 0.02 Cumulative incidence (%) 10 0 0 6 12 18 24 30 36 Month Dawson-Hughes B, et al. N Engl J Med1997;337:670-6

  12. Vitamin D Insufficiency (<30 ng/mL): Prevalence by Latitude n=259/532 (48.7%) 42 N n=342/642 (53.3%) 35 N n=198/362 (54.7%) P = NS for Test of Trend Holick MF, et al. J Clin Endocrinol Metab 2005;90:3215-24

  13. Estrogen Treatment (ET) • Several approved oral and transdermal preparations available • Approved for prevention (not treatment) of osteoporosis • Treats symptoms of low estrogen levels • Skeletal effects • Decrease in biochemical markers of 50-60% • 2-year BMD increase of 4-6% at hip and spine • Decreased incidence of vertebral and hip fractures (34%) after 5 years in the WHI • Effects in women with osteoporosis have not been evaluated in randomized controlled trials Writing Group for the WHI. JAMA 2002;288:321

  14. Estrogen Treatment (ET) Current Status of Estrogen for Osteoporosis • Long-term use not recommended • Adverse effects may outweigh benefits Writing Group for the WHI. JAMA 2002;288:321

  15. Calcitonin • Calcitonin: 200 units daily by nasal spray • Approved for treatment (not prevention) • Skeletal effects: • Decrease in biochemical markers of 20% • Small effect (1-2%) on bone density in spine • Reduced incidence of vertebral fractures (36%) in women with pre-existing vertebral fractures • No effect on non-vertebral or hip fractures has been observed • Adverse effects: nasal stuffiness Chesnut CH, et al. Am J Med 2000;109:267-276

  16. Raloxifene • Raloxifene 60 mg daily • Approved for both prevention and treatment • Skeletal effects: • Decrease in biochemical markers of 30% • 3-year BMD increases of 2-3% at hip and spine • Decreased incidence of vertebral fractures (30-50%) in women with pre-existing vertebral fractures or low bone density. No effect on non-vertebral or hip fractures has been observed. • Adverse effects: hot flashes, venous thrombosis, leg cramps • Extra-skeletal effects: Reduction in breast cancer Ettinger B, et al. JAMA 1999;282:637-645

  17. BisphosphonatesRisedronate, Alendronate and Ibandronate Three bisphosphonates are available for prevention and treatment of osteoporosis—in daily oral, intermittent oral, and intermittent parenteral formulations: • Risedronate (Actonel®): 5 mg daily or 35 mg weekly • Alendronate (Fosamax®): 10 mg daily or 70 mg weekly for treatment, 5 mg daily or 35 mg weekly for prevention; available as oral suspension • Ibandronate (Boniva® ): 2.5 mg daily or 150 mg monthly by mouth; 3 mg iv over 15-30 seconds every 3 months

  18. BisphosphonatesRisedronate, Alendronate and Ibandronate • Approved Indications • Treatment and prevention of postmenopausal osteoporosis (ibandronate, risedronate, alendronate) • Treatment and prevention of glucocorticoid-induced osteoporosis (risedronate) • Treatment of glucocorticoid-induced osteoporosis (alendronate) • Treatment of men with low bone density (alendronate)

  19. BisphosphonatesRisedronate, Alendronate and Ibandronate • Approval for these diverse indications was based on studies performed with daily oral bisphosphonate administration • No studies of approved intermittent dosing (weekly, quarterly, monthly) were designed with a primary fracture endpoint; all examined the surrogates BMD and biochemical markers • Intermittent ibandronate dosing regimen with extended dose-free intervals demonstrated 50% fracture reduction at 3 years as primary end point

  20. BMD Changes with Bisphosphonates • There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction • In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made

  21. Extended Dosing • Extended dosing is based on the hypothesis that the intermittent administration of a medication will have a durable clinical benefit • That durable benefit would ideally be assessed by a “hard” clinical endpoint such as fracture protection • Absent that clinical endpoint, the benefit could be assessed indirectly by pharmacokinetics and the effects of treatment on surrogate endpoints such as BMD and biochemical markers of turnover

  22. Extended Dosing • A successful extended dosing regimen would presumably show an effect on biochemical markers of bone turnover—but it’s not obvious a priori what the ideal marker profile might be • A successful dosing regimen would also presumably show an effect on BMD at diverse sites—but it’s again not obvious what the ideal BMD response might be

  23. Extended Dosing • The “bridging” approach has been based on the assumption that extended dosing will reduce fracture risk if the extended dosing affects the surrogates—markers and BMD—in a fashion that is “non-inferior” to standard, daily dosing that has been proven to reduce fracture risk

  24. Bridging From Daily to LessFrequent Dosing Regimens On this basis, weekly alendronate1 and risedronate2 and monthly ibandronate are assumed to be able to produce similar antifracture efficacy to their respective daily regimens Daily bisphosphonate regimen (with proven antifracture efficacy) Regimens shown to be equivalent in terms of lumbar spine BMD at 1 year, using non-inferiority or equivalence tests Less frequent bisphosphonate dosing regimen • Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12. • Brown JP, et al. Calcif Tissue Int. 2002;71:103-111. • Miller P et al, J BoneMin Res, 2005, 20, 8, 1315-1322

  25. BMD Results for Alendronate

  26. Precedent for Applying the Bridging Concept: Alendronate • Equivalence study comparing 35 mg twice weekly and 70 mg once weekly to 10 mg daily alendronate • Inclusion criteria • Females 40-90 years old • ≥ 2 years since menopause • Lumbar spine or femoral neck T-score ≤ -2.5, or prior vertebral or hip fracture • Daily supplementation with 500 mg calcium and 250 IU vitamin D • 30-minute post-dose fast Alendronate 10 mg daily oral Primary endpoint = equivalence of lumbar spine BMD at Year 1 Alendronate 70 mg weekly oral In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

  27. Alendronate: BMD Results (Daily vs Weekly) Year 1 8.0 7.0 10 mg Daily at Year 1 70 mg Once Weekly at Year 1 6.0 5.0 Mean % Changein BMD From Baseline 4.0 3.0 5.4 5.1 4.4 2.0 3.9 3.1 2.9 2.9 2.3 1.0 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter • Equivalence demonstrated between weekly and daily dosing regimens. In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

  28. Alendronate: BMD Results (Daily vs Weekly) Year 1&2 10 mg Daily at Year 11 10 mg Daily at Year 22 70 mg Once Weekly at Year 11 70 mg Once Weekly at Year 22 8.0 7.4 6.8 7.0 6.1 5.9 6.0 5.0 4.3 4.1 Mean % Changein BMD From Baseline 3.5 4.0 3.3 3.0 5.4 5.1 4.4 2.0 3.9 3.1 2.9 2.9 2.3 1.0 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. 1. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12. 2. Rizzoli R, et al. J Bone Miner Res. 2002;17:1988-1996.

  29. BMD Results with Risedronate

  30. Precedent for Applying the Bridging Concept: Risedronate Risedronate 5 mg daily oral • Non-inferiority study comparing 35 mg and 50 mg once-weekly to 5 mg daily risedronate • Inclusion criteria • Females ≥ 50 years of age • Postmenopausal ≥ 5 years • Lumbar spine or femoral neckT-score ≤ -2.5; or lumbar spineT-score ≤ -2.0 and at least one prevalent vertebral fracture • Daily supplementation with 1000 mg calcium and 500 IU vitamin D* • 30-minute post-dose fast Primary endpoint = non-inferiority of lumbar spine BMD at Year 1 Risedronate 35 mg weekly oral * For patients with low serum levels of vitamin D at baseline. In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

  31. Risedronate: BMD Results (Daily vs Weekly) Year 1 5 mg Daily at Year 1 35 mg Once Weekly at Year 1 8.0 7.0 6.0 5.0 Mean % Changein BMD From Baseline 4.0 3.0 4.0 3.9 3.3 2.0 3.0 2.5 2.4 2.1 1.9 1.0 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter • Equivalence demonstrated between weekly and daily dosing regimens. In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.

  32. Risedronate: BMD Results (Daily vs Weekly) Year 1&2 5 mg Daily at Year 11 5 mg Daily at Year 22 35 mg Once Weekly at Year 11 35 mg Once Weekly at Year 22 8.0 7.0 5.2 6.0 4.7 4.7 5.0 4.2 Mean % Changein BMD From Baseline 3.4 4.0 3.0 2.5 3.0 1.9 4.0 3.9 3.3 2.0 3.0 2.5 2.4 2.1 1.9 1.0 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. 1. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111. 2. Harris ST, et al. Curr Med Res Opin. 2004;20:757-764.

  33. BMD Results for Ibandronate

  34. Applying the Bridging Concept: Ibandronate • Non-inferiority study comparing 100 mg and 150 mg once-monthly to 2.5 mg daily ibandronate • If non-inferiority was demonstrated, a pre-planned statistical superiority test was conducted • Inclusion criteria • Females 55-80 years old • ≥5 years since menopause • Mean lumbar spine (L2–L4) BMD T-score <–2.5 and ≥–5.0 • Daily supplementation with 500 mg calcium and 400 IU vitamin D • 60-minute post-dose fast Ibandronate 2.5 mg oral daily Primary endpoint = non-inferiority of lumbar spine BMD at Year 1 Ibandronate 150 mg once-monthly oral Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.

  35. Ibandronate : BMD Results (Daily vs Monthly) Year 1 Ibandronate 2.5 mg Daily at Year 1 Ibandronate 150 mg Monthly at Year 1 8.0 7.0 6.0 Mean % Changein BMD From Baseline 5.0 4.0 3.0 4.8 4.6 3.7 2.0 3.2 3.0 2.2 1.7 2.0 1.0 (316) (314) (314) (315) (316) (316) (315) (315) 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter Year 1 P=0.001 P<0.0001 P=0.09 P<0.0001 vs 2.5 mg daily • Non-inferiority was demonstrated between monthly and daily dosing regimens. • The monthly dosing regimen was statistically superior at lumbar spine, total hip, and trochanter. Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110. Per-protocol population (n).

  36. Ibandronate: BMD Results (Daily vs Monthly) Year 1&2 2.5 mg Daily at Year 1 150 mg Monthly at Year 1 150 mg Monthly at Year 2 2.5 mg Daily at Year 2 8.0 6.6 7.0 6.2 6.0 5.0 (291) (289) Mean % Changein BMD From Baseline 5.0 4.2 4.0 (294) 4.0 (292) 3.1 (289) 3.0 2.5 (292) (289) 4.8 4.6 1.9 (292) 3.7 2.0 3.2 3.0 2.2 1.7 2.0 1.0 (316) (314) (314) (315) (316) (316) (315) (315) 0.0 Lumbar Spine Total Hip Femoral Neck Trochanter Year 1 P=0.001 P<0.0001 P=0.09 P<0.0001 Year 2 P<0.0001 P<0.0001 P=0.0002 P<0.0001 vs 2.5 mg daily Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110. Per-protocol population (n).

  37. Ibandronate: Summary of Daily vs Monthly BMD Results • Non-inferiority demonstrated between monthly and daily dosing regimens • The monthly dosing regimen was statistically superior to the daily dosing regimen in terms of BMD elevations across all sites at Year 2, per pre-planned analysis • The increase in BMD between years 1 and 2 was statistically significant across all sites Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

  38. Observations: BMD Changes There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111. Harris ST, et al. Curr Med Res Opin. 2004;20:757-764.Rizzoli R, et al. J Bone Miner Res. 2002;17:1988-1996.Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12. Data on file (Reference # 161-094, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.

  39. Responders Analysis

  40. Responders Analysis • Categorization of responders is an attempt at differentiating success at increasing or maintaining BMD (responders) from those with decreasing BMD • MOBILE and FACT studies looked at responders • % patients with lumbar spine or hip trochanter BMD changes at baseline1-3 • There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of BMD changes or fracture reduction • In the absence of head-to-head clinical studies, comparisons of efficacy such as BMD changes and fracture reduction between bisphosphonates should not be made MOBILE – Monthly Oral iBandronate In LadiEs; FACT – Fosamax Actonel Comparison Trial. Fosamax is a registered trademark of Merck & Co., Inc. Actonel is a registered trademark of Procter & Gamble Pharmaceuticals Inc. 1. Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151. 2. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. 3. Data on file (Reference # 161-092) Hoffmann-La Roche Inc., Nutley, NJ 07110.

  41. FACT: Results Year 1 % Patients With Lumbar Spine and Trochanter BMD Values ≥ Baseline 87.3%* 84.5%* 75.6% 67.8% Risedronate35 mg/week Risedronate35 mg/week Alendronate70 mg/week Alendronate70 mg/week 100 80 60 Patients (%) 40 20 Lumbar Spine Trochanter 0 In the absence of head-to-head studies, the results obtained from different clinical trials should not be compared. * P<0.001 vs risedronate. Modified intent-to-treat population. Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151.

  42. MOBILE: Results Year 1 % Patients With Lumbar Spine and Trochanter BMD Values ≥ Baseline 92.4%** 90.8%* 83.8% 80.0% n=314 n=314 n=315 n=316 150 mg Monthly 2.5 mg Daily 150 mg Monthly 2.5 mg Daily 100 80 60 Patients (%) 40 Lumbar Spine Trochanter 20 0 * P= 0.008vs 2.5 mg; **P<0.001 vs 2.5 mg. Per-protocol population. Data from one or both sources. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. Data on file (Reference # 161-094) Hoffmann-La Roche Inc., Nutley, NJ 07110.

  43. Daily and Monthly Oral Ibandronate • The MOBILE study examined BMD and biochemical marker changes with daily (2.5 mg) and monthly (150 mg) ibandronate therapy over 1 and 2 years • The changes in BMD with monthly therapy were superior to those seen with daily treatment Miller PD, et al. J Bone Miner Res 2005;20:1315-22 Reginster JY, et al. Ann Rheum Dis 2006;65:654-61

  44. Relationship between change in BMD and risk of vertebral fracture: the BONE study 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 Placebo Oral daily and intermittentibandronate Fracture rate/per 100 patients –4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9 BMD change (%) Wasnich R, et al. Osteoporos Int 2003;14 (Suppl. 7):S76(Abstract P272)

  45. BisphosphonatesRisedronate, Alendronate and Ibandronate • None of the approved intermittent bisphosphonate regimens (weekly, monthly or quarterly) has demonstrated protection against vertebral or nonvertebral fractures • Each intermittent regimen was approved on the basis of changes in BMD and biochemical markers over 1-2 years that were non-inferior (alendronate, risedronate) or superior (ibandronate) to those observed with standard daily therapy with the same agent over that same study period

  46. BisphosphonatesRisedronate, Alendronate and Ibandronate Rationale for Approval of Intermittent Regimens • In each case, daily oral bisphosphonate therapy had already demonstrated fracture protection in other trials • It was assumed that, if changes in the surrogates were comparable to daily therapy in a head-to-head trial, intermittent therapy would also be effective for fracture protection

  47. BisphosphonatesRisedronate and Alendronate Effects on Markers and Fracture Prevention • Increases of 5-8% in bone density in the spine, and 3-5% in the hip after 3 years • Reduced incidence of vertebral fractures by 40-65% • Reduced nonvertebral fractures (30-40%), including hip fractures (40-60%; alendronate), in women with osteoporosis

  48. Control Alendronate 10 mg 10 8 6 Mean % Change from Baseline 4 2 0 -2 6 12 18 24 30 36 Month Osteoporosis Therapy: Bisphosphonates Spinal BMD Change with Daily Alendronate Liberman UA, et al. N Engl J Med 1995;333:1437-43

  49. Control Risedronate 5 mg 10 8 6 Mean % Change from Baseline 4 2 0 6 12 18 24 30 36 Month Osteoporosis Therapy: Bisphosphonates Spinal BMD Change with Daily Risedronate Harris ST, et al. JAMA 1999; 282:1344-52

  50. BisphosphonatesIbandronate Effects on Bone Markers and Fractures • Increases of 6% in bone density in the spine and increases of 3-5% in the hip after 3 years of daily treatment • Reduced incidence of vertebral fractures by 50%; reduction in non-vertebral fractures in post-hoc analysis only in patients with BMD < -3.0

More Related